Molecular Testing in Metastatic Gastric/GEJ Cancer

David Ilson, MD, PhD: At the current time, if you’re dealing with a patient with locally advanced disease, molecular testing does not play a clear role. It really does not impact choice of therapy. For metastatic disease, on the other hand, molecular testing does have an impact. Although we are in the era of whole-exome sequencing and next-generation sequencing of cancers, it does still play a limited role in identifying treatments for gastric cancer. The one that is standard is HER2 testing.

In metastatic disease, if a patient is HER2-positive, we include trastuzumab as part of chemotherapy. Now, we have to consider in metastatic disease either MSI [microsatellite instability] testing, DNA mismatch repair protein testing, or PD-L1 testing. We now have evidence that anti–PD-1 drugs, particularly pembrolizumab, have a signal of activity in PD-L1–positive gastric cancers in refractory disease and have even more significant activity in MSI-high or DNA mismatch repair-deficient gastric cancers.

Up front, we do HER2 testing. That has an impact on initial treatment of metastatic disease. When they become refractory to chemotherapy, we now have regulatory approval of pembrolizumab for either PD-L1–positive or MSI-high gastric cancers. In terms of everything else that we see in genomic sequencing, it’s interesting. It’s a research question. Maybe we can identify in 1% of patients some mutation such that they might be an appropriate candidate for a trial. But typically, we find p 53 mutations, or we find an amplification of receptor-associated tyrosine kinases, of which the only relevant one is HER2. Although genomic testing is becoming part of standard practice, in reality there are really 3 things that we need to test for: HER2, MSI, and PD-L1.

When we suspect gastric cancer in young patients or any patient under the age of 50 or patients with a significant history of gastric cancer in their family, we should think about CDH1 or hereditary diffuse gastric cancer. That’s not a subtle presentation in a family. Typically, these are patients who develop gastric cancer in their 30s and 40s. We see it generation after generation. Just because someone is under the age of 50 doesn’t mean they have CDH1-mutated gastric cancer. There’s also an association with lobular breast cancer. So that’s not routinely tested for.

We do have considerations for using genetic testing for and counseling any patient who develops gastric cancer under the age of 40 to 50, but usually we’re not going to find a heritable mutation unless there’s a family history. CDH1-mutated gastric cancer is relatively rare. Other rare familial gastric cancer syndromes include Lynch syndrome, where we see the association with colorectal cancer and gynecologic cancers in women, and BRCA-mutated breast cancer, which has an associated increased risk in gastric cancer.

We talked about nonpolyposis Lynch syndrome. There are also the polyposis syndromes: Peutz-Jeghers, juvenile polyposis, and FAP [familial adenomatous polyposis] all have associated increased risks for developing gastric cancer. But these are all rare. Typically, we would consider genetic testing for a young patient or if there’s a strong family history, but even in a young patient, we’re not likely to find a mutation. There is occasionally a situation where that patient is the index member of the family. With young patients, we do test. For older patients, we would test only in the context of a strong family history.

Transcript Edited for Clarity

Transcript:

David Ilson, MD, PhD: At the current time, if you’re dealing with a patient with locally advanced disease, molecular testing does not play a clear role. It really does not impact choice of therapy. For metastatic disease, on the other hand, molecular testing does have an impact. Although we are in the era of whole-exome sequencing and next-generation sequencing of cancers, it does still play a limited role in identifying treatments for gastric cancer. The one that is standard is HER2 testing.

In metastatic disease, if a patient is HER2-positive, we include trastuzumab as part of chemotherapy. Now, we have to consider in metastatic disease either MSI [microsatellite instability] testing, DNA mismatch repair protein testing, or PD-L1 testing. We now have evidence that anti–PD-1 drugs, particularly pembrolizumab, have a signal of activity in PD-L1–positive gastric cancers in refractory disease and have even more significant activity in MSI-high or DNA mismatch repair-deficient gastric cancers.

Up front, we do HER2 testing. That has an impact on initial treatment of metastatic disease. When they become refractory to chemotherapy, we now have regulatory approval of pembrolizumab for either PD-L1–positive or MSI-high gastric cancers. In terms of everything else that we see in genomic sequencing, it’s interesting. It’s a research question. Maybe we can identify in 1% of patients some mutation such that they might be an appropriate candidate for a trial. But typically, we find p 53 mutations, or we find an amplification of receptor-associated tyrosine kinases, of which the only relevant one is HER2. Although genomic testing is becoming part of standard practice, in reality there are really 3 things that we need to test for: HER2, MSI, and PD-L1.

When we suspect gastric cancer in young patients or any patient under the age of 50 or patients with a significant history of gastric cancer in their family, we should think about CDH1 or hereditary diffuse gastric cancer. That’s not a subtle presentation in a family. Typically, these are patients who develop gastric cancer in their 30s and 40s. We see it generation after generation. Just because someone is under the age of 50 doesn’t mean they have CDH1-mutated gastric cancer. There’s also an association with lobular breast cancer. So that’s not routinely tested for.

We do have considerations for using genetic testing for and counseling any patient who develops gastric cancer under the age of 40 to 50, but usually we’re not going to find a heritable mutation unless there’s a family history. CDH1-mutated gastric cancer is relatively rare. Other rare familial gastric cancer syndromes include Lynch syndrome, where we see the association with colorectal cancer and gynecologic cancers in women, and BRCA-mutated breast cancer, which has an associated increased risk in gastric cancer.

We talked about nonpolyposis Lynch syndrome. There are also the polyposis syndromes: Peutz-Jeghers, juvenile polyposis, and FAP [familial adenomatous polyposis] all have associated increased risks for developing gastric cancer. But these are all rare. Typically, we would consider genetic testing for a young patient or if there’s a strong family history, but even in a young patient, we’re not likely to find a mutation. There is occasionally a situation where that patient is the index member of the family. With young patients, we do test. For older patients, we would test only in the context of a strong family history.